Genome analysis provides an estimation that the total gene number in human genome is about 22,000 and an anticipation that the alternative splicing mechanism is carried out in 50 to 60% of the number of genes. Alternative splicing mechanism is a reasonable and efficient gene expression regulation mechanism, which involves a plurality of ways of removing introns upon a splicing where an intron region is cleaved from an RNA precursor, a gene product, and two exons upstream and downstream linked each other, so that a single gene can produce a plurality of proteins having different localization and properties. With respect to how the information of presumably 100,000 or more proteins is coded in 22,000 genes and expressed in a human body, the alternative splicing is considered to make up the gap in number.
On the other hand, it has been shown that canceration of cells be caused by gene mutation or abnormal gene expression regulation. Abnormal occurrence of splice variants due to abnormal regulation of alternative splicing in intracellular gene products such as transcription products and translation products thereof may be one of factors of canceration of cells.
For example, human cell adhesion molecule (hyaluronic acid receptor), CD44, has 20 types of identified splice variant transcription products and it has been elucidated that the expression ratios of splice variant transcription products significantly differ: at least between cancerous pleural effusion and non-cancerous pleural effusion; and between urine from a patient with bladder cancer and urine from a patient without cancer. The expression ratios of the splice variant transcription products are also applied to clinical tests as a method of distinguishing cancerous cells from normal cells.
Canceration of cells is a phenomenon caused by abnormal expression of a plurality of genes and the mechanism thereof remains to be elucidated. It is known that mutations of genes and expression abnormalities that are involved in canceration of cells are varied depending on tissues from which cancerous cells are derived and degree of canceration of cells.
Therefore, besides the above-mentioned CD44, new cancer markers for use in cancer diagnosis well matched for various cancers are required, which can also be utilized as the targets in drug discovery. In particular, there are expectations, properly and accurately understanding the conditions of cancer cells causing cancer diseases, that cancer markers be provided useful for obtaining the correlation between different conditions of cancer cell and cancer disease.
Regarding cancer markers, the Patent Document 1 described below discloses novel ATPase-like polypeptide and its DNA expressed in a human monocyte cell line THP-1. The polypeptide is a 10-transmembrane protein having three P-type ATPase regions in the cell membrane and is a novel ATPase-like polypeptide having a 1192 amino acid sequence or a deleted mutant (splice variant) having a 1129 amino acid sequence in which 63 amino acids in the cell membrane is deleted. The polypeptide is confirmed to express with increased ratios in cancer cells, in particular gastric cancer cells, so that the polypeptide is useful as a novel cancer marker.
Regarding application of splice variants to pharmaceuticals and diagnosis of disease, Patent Document 2 discloses an identification of novel splice variant of MAP kinase p38α resulting from alternative splicing, cloning a gene coding the variant and an elucidation of the structure and function of the gene.
On the other hand, PTCH1 gene, which is one of Hedgehog signal genes, is known to play an important role in the developmental process of multicellular organisms and in the maintenance of functions of adults. In humans, PTCH1 gene is known to be a causative gene for genetic diseases accompanied by congenital malformation such as basal cell nevus syndrome. PTCH1 gene is also reported to be involved in basalioma, medulloblastoma, etc. as a cancer suppressor gene (see Patent Documents 1 and 2 below).    Patent Document 1: JP 2003-164288 A    Patent Document 2: JP 2003-135073 A    Non Patent Document 1: Kappler R. et al. Oncogene. 2004 Nov. 18; 23(54): p 8785-95    Non Patent Document 2: Chang-Claude J. et al. Int. J. Cancer 2003 Mar. 1; 103(6): p 779-83